Hypertensive heart disease (HHD) results from long-standing hypertension (HTN) and manifests early as left ventricular hypertrophy (LVH) and/or left ventricular diastolic dysfunction (LVDD). Although initially an adaptive response, over-time LVH and LVDD become maladaptive leading to ventricular enlargement, systolic dysfunction (LVSD), and/or dilated cardiomyopathy/heart failure. Our group and others have shown that alterations in myocardial fatty acid (FA) metabolism are important determinants of the presence and development of LVH, LVDD, and LVSD in animal models and in humans. Long-chain fatty acids (LCFA) are an essential source of energy for the heart. Although some LCFAs diffuse passively across the sarcolemma, a protein-facilitated transporter, the fatty acid translocase (FAT or CD36) confers tissue-specific expression entrained to substrate availability. The CD36-PPAR1/3-PGC11 FA metabolism regulatory pathway plays an important role in the etiology of cardiovascular diseases, especially LVH and cardiomyopathy. Thus, the hypothesis of the proposal is that genetic variations of FA metabolism pathway genes modulate the phenotypic expression of HHD in humans. This hypothesis will be tested as follows:
Specific Aim 1) Identify CD36 tagSNPs associated with the presence and severity of individual HHD traits (i.e. LV mass, LV size, and indices of LV systolic and diastolic function) in a Caucasian and an African-American cohort using conventional regression analyses controlling for potential confounders;
and Specific Aim 2) Investigate modifying factors of latent HHD-related phenotypes by exploring gene-gene and gene-environment interactions using innovative data-reduction methods including factor analysis and Bayesian network-based decomposable graphical models. Gene-gene interactions will be tested between CD36 and 3 regulatory pathway genes involved in FA metabolism (i.e., PPAR1, PPAR3, and PGC11). The results of this research will generate robust data in support of a subsequent submission by this new investigator of an R01 proposal to perform deep resequencing of high-risk haplotypes, to refine the analytic techniques, and to further validate the findings of the R21 pilot study. This research is designed to provide an understanding of the association between gene regulation of the cardiac hypertrophic response and the associated phenotypic changes in myocardial metabolism. Allowing better elucidation of the mechanisms that lead to the transition from HTN to HHD phenotypes and their associated morbidity may allow identification of individuals at high risk of cardiovascular morbidity and mortality and may facilitate future efforts at identifying novel therapeutic strategies in the prevention and/or treatment of HHD.

Public Health Relevance

Hypertensive heart disease, which results from long-standing hypertension and manifests early as left ventricular hypertrophy and/or left ventricular diastolic dysfunction (LVDD), is responsible for significant cardiovascular morbidity and mortality including progression to heart failure. The purpose of this research is to explore the potential role of variants in myocardial metabolism genes to modulate hypertensive heart disease traits in a biracial population by use of sophisticated techniques capable of analyzing complex genetic and phenotype data.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL094668-02
Application #
7751331
Study Section
Special Emphasis Panel (ZRG1-SBIB-P (02))
Program Officer
Adhikari, Bishow B
Project Start
2008-12-15
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2011-11-30
Support Year
2
Fiscal Year
2010
Total Cost
$152,000
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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de las Fuentes, Lisa; Yang, Wei; Dávila-Román, Victor G et al. (2012) Pathway-based genome-wide association analysis of coronary heart disease identifies biologically important gene sets. Eur J Hum Genet 20:1168-73
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Yang, Wei; de las Fuentes, Lisa; Dávila-Román, Victor G et al. (2011) Variable set enrichment analysis in genome-wide association studies. Eur J Hum Genet 19:893-900
de Las Fuentes, Lisa; Spence, Karen E; Dávila-Román, Victor G et al. (2010) Are normative values for LV geometry and mass based on fundamental imaging valid with use of harmonic imaging? J Am Soc Echocardiogr 23:1317-22
de las Fuentes, Lisa; de Simone, Giovanni; Arnett, Donna K et al. (2010) Molecular determinants of the cardiometabolic phenotype. Endocr Metab Immune Disord Drug Targets 10:109-23
Juang, Jyh-Ming Jimmy; de Las Fuentes, Lisa; Waggoner, Alan D et al. (2010) Association and interaction of PPAR-complex gene variants with latent traits of left ventricular diastolic function. BMC Med Genet 11:65
Subherwal, Sumeet; de las Fuentes, Lisa; Waggoner, Alan D et al. (2010) Central aortic pressure is independently associated with diastolic function. Am Heart J 159:1081-8

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